DLG1/SAP97 modulates transforming growth factor alpha bioavailability.
TGFalpha and its receptor EGFR participate in the development of a wide range of tumors including gliomas, the main adult primary brain tumors. TGFalpha soluble form results from the cleavage by the metalloprotease TACE/ADAM17 of the extracellular part of its transmembrane precursor, pro-TGFalpha. To gain insights into the mechanisms underlying TGFalpha bioavailability, a yeast two-hybrid screen was performed to identify proteins interacting with pro-TGFalpha intracellular domain (ICD). DLG1/SAP97 (Discs Large Gene 1 or Synapse Associated Protein 97) was found to interact with both pro-TGFalpha and TACE ICDs through distinct PDZ domains. An in vivo pro-TGFalpha-DLG1-TACE complex was detected in U251 glioma cells and in gliomas-derived tumor initiating cells. Interaction between DLG1 and TACE diminished in response to stimulations promoting pro-TGFalpha shedding. Manipulation of DLG1 levels revealed dual actions of DLG1 on pro-TGFalpha shedding, favoring approximation of pro-TGFalpha and TACE, while limiting TACE full shedding activity. These results show that DLG1 participates in the control of TGFalpha bioavailability through its dynamic interaction with the growth factor precursor and TACE.
Surena
Anne-Laure
AL
Inserm, UMR894, University of Paris 5, 75014 Paris, France.
de Faria
Giselle P
GP
Studler
Jeanne-Marie
JM
Peiretti
Franck
F
Pidoux
Morgane
M
Camonis
Jacques
J
Chneiweiss
Hervé
H
Formstecher
Etienne
E
Junier
Marie-Pierre
MP
D051722:ADAM Proteins / Q000737:chemistry / Q000378:metabolism; D000072198:ADAM17 Protein; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D000074288:Discs Large Homolog 1 Protein; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000737:chemistry / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D011498:Protein Precursors; D016211:Transforming Growth Factor alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human